Zepzelca
lurbinectedin
Species
MonkeyRatDog
Longest study
24 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat, dog and cynomolgus monkey
“The Sprague Dawley rat, Beagle dog and Cynomolgus monkey were the main species used for toxicological assessment of lurbinectedin.”
Why that species
Monkey chosen as non-rodent because its metabolism was more similar to human than other non-rodents
“Despite using dogs in the initial 4-week toxicology studies, the Applicant utilized the monkey in the 13-week non-rodent toxicology study due to metabolic data suggesting that monkey metabolism was more similar to human than other tested non-rodent species.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Intravenous administration of PM01183 at the dose of 0.125 mg/kg every 3 weeks for 8-cycles was not tolerated by Cynomolgus monkeys”
Species: general tox
Rat, beagle dog and cynomolgus monkey
“The Sprague Dawley rat, Beagle dog and Cynomolgus monkey were the main species used for toxicological assessment of lurbinectedin.”
Species: DART
Rat only (preliminary single-dose EFD study); no fertility or pre/postnatal studies
“Given its mechanism of action as a genotoxic agent targeting rapidly dividing cells, FDA would not generally request an embryofetal development study, however, the Applicant did conduct a preliminary single dose, single-dose level embryo-fetal development study in rats.”
Species: carcinogenicity
Not conducted (advanced cancer patient population)
“The Applicant did not conduct carcinogenicity studies based on the proposed patient population.”
Surrogate used in
No surrogate used; lurbinectedin tested directly
“The Sprague Dawley rat, Beagle dog and Cynomolgus monkey were the main species used for toxicological assessment of lurbinectedin.”
Study lengthopen answer page →
Longest pivotal study
24 (8-cycle q3w rat and monkey)
“Toxicology program for lurbinectedin was investigated in rats, dogs and NHPs for up to 24 weeks.”
Pivotal GLP studies
8-cycle (every 3 weeks) rat and monkey studies
“The highest doses used in the rat and monkey 8-cycle studies resulted in exposures approximately 8 times lower than the human exposure at the recommended dose of 3.2 mg/m2 once every 3 weeks.”
Route in tox
Intravenous bolus
“Route of administration: Bolus intravenous”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; positive in mouse lymphoma TK assay; genotoxic
“Lurbinectedin was negative in the in vitro Ames assay but induced mutations in the mouse TK lymphoma assay, confirming that, as expected based on its mechanism of action, lurbinectedin is genotoxic.”
Carcinogenicity
Not conducted (advanced cancer patient population)
“The Applicant did not conduct carcinogenicity studies based on the proposed patient population.”
Reproductive & developmental
Preliminary single-dose rat EFD study only: no viable fetuses
“Six pregnant rats received a single lurbinectedin dose of 0.1 mg/kg (0.6 mg/m2 ) or vehicle control on Day 10. There were no viable fetuses in lurbinectedin-treated dams.”
Safety pharmacology
No clear acute cardiovascular, CNS or respiratory effects in any species
“There were no clear acute effects on cardiovascular, CNS, or respiratory parameters in any species.”
Genotox: Ames
Negative
“Lurbinectedin was negative in the in vitro Ames assay but induced mutations in the mouse TK lymphoma assay, confirming that, as expected based on its mechanism of action, lurbinectedin is genotoxic.”
Genotox: in vitro mammalian
Mouse lymphoma TK assay: positive (mutagenic)
“Lurbinectedin was negative in the in vitro Ames assay but induced mutations in the mouse TK lymphoma assay, confirming that, as expected based on its mechanism of action, lurbinectedin is genotoxic.”
Genotox: in vivo
Not conducted (acceptable under ICH S2 for strongly cytotoxic compounds)
“In vivo testing was not conducted, but this is acceptable under ICH S2 for strongly cytotoxic compounds targeting rapidly dividing cells.”
Carcinogenicity model
Not conducted (advanced cancer patient population)
“The Applicant did not conduct carcinogenicity studies based on the proposed patient population.”
Carcinogenicity timing
Not conducted given the advanced-cancer patient population
“The Applicant did not conduct carcinogenicity studies based on the proposed patient population.”
hERG / QT
hERG IC50 8.8 μM (~6900 ng/mL), far above patient Cmax (~130 ng/mL)
“with estimated IC50 of 8.8 μM (~ 6900 ng/mL), which is far greater than the Cmax-values achieved in patients (~ 130 ng/mL) treated at the proposed clinical dosing (3.2 mg/m2, i.v., 1-h infusion).”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Zepzelca don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oncology small molecules (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Injection-site lesions and bone marrow suppression (transient leukopenia, mild anemia) in all species (FDA multi-discipline review, p. 28)
NOAEL / key findings
Injection-site lesions and bone marrow suppression (transient leukopenia, mild anemia) in all species
“The major toxicological findings in all three tested species were injection site findings including hemorrhage, edema, inflammation, thrombosis, and necrosis and bone marrow effects leading to transient leukopenia and mild anemia with decreased cellularity in the bone marrow.”
Risksopen answer page →
Immune & cytokine safety
Lymphocyte and neutrophil decreases suggest a general decrease in immune responsiveness
“dose-dependent decreases in lymphocytes and neutrophils following repeated lurbinectedin administration suggest that there may have been a general decrease in immune responsiveness.”
Biodistribution & persistence
Highest tissue levels in spleen, lymph nodes, liver, thyroid, kidney, lung, skin; lowest in brain and testes
“The lowest radioactivity concentrations were detected in the brain (<5 and <2.3 ng-eq/g for male and female rats, respectively) and testes (<12 ng-eq/g). The highest values of total activity were in spleen, followed by lymph nodes, liver, thyroid glands, kidney, lung and skin.”
Modality-specific risk
Embryofetal lethality (no viable fetuses in rat EFD study)
“There were no viable fetuses in lurbinectedin-treated dams. A warning for embryo-fetal toxicity is included in the label”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
- Myelosuppression
- Hepatotoxicity
- Extravasation Resulting in Tissue Necrosis
- Rhabdomyolysis
- Embryo-Fetal Toxicity
CytopeniasHepatotoxicityMusculoskeletalEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country not stated; first-in-human multicenter dose escalation in patients with advanced solid tumors
“New IND submitted for Protocol PM1183-A-001-08, the first-in-human (FIH) study with lurbinectedin entitled, “Phase I, multicenter, open-label, dose-escalating, clinical and pharmacokinetic study of PM01183 in patients with advanced solid tumors.””
Repeat-dose tox before first-in-human
4-cycle (dosing every 3 weeks) rat and dog studies with 3-week recovery, reviewed under the original IND to support clinical dosing
“The Applicant also conducted 4-cycle (dosing once every 3 week) toxicology studies with 3-week recovery periods in rats and dogs. These studies were submitted to FDA and reviewed by Dr. Brenda J. Gehrke under the original IND to support clinical dosing.”
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Zepzelca don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oncology small molecules (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Injection-site lesions and bone marrow suppression (transient leukopenia, mild anemia) in all species (FDA multi-discipline review, p. 28)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Every-3-week multi-cycle IV studies in cynomolgus monkey and rat; recovery sacrifice on Day 169, 21 days after the last cycle
“Day 169 (21 days after the last cycle of treatment) – treatment related changes in the hematopoietic system (bone marrow, thymus) and in the injection site were reversible or were undergoing reversal.”
Pivotal GLP studies
8-cycle (every 3 weeks) rat and monkey studies
“The highest doses used in the rat and monkey 8-cycle studies resulted in exposures approximately 8 times lower than the human exposure at the recommended dose of 3.2 mg/m2 once every 3 weeks.”
DART package
Species: DART
Rat only (preliminary single-dose EFD study); no fertility or pre/postnatal studies
“Given its mechanism of action as a genotoxic agent targeting rapidly dividing cells, FDA would not generally request an embryofetal development study, however, the Applicant did conduct a preliminary single dose, single-dose level embryo-fetal development study in rats.”
Reproductive & developmental
Preliminary single-dose rat EFD study only: no viable fetuses
“Six pregnant rats received a single lurbinectedin dose of 0.1 mg/kg (0.6 mg/m2 ) or vehicle control on Day 10. There were no viable fetuses in lurbinectedin-treated dams.”
PPND / ePPND: when
Not conducted; not needed for advanced cancer (ICH S9)
“Consistent with the principles discussed in the ICH S9 guidance for industry, the Applicant did not conduct fertility or pre- and post-natal development studies to support the the submission of an NDA for a drug intended for the treatment of patients with advanced cancer.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer patient population)
“The Applicant did not conduct carcinogenicity studies based on the proposed patient population.”
Carcinogenicity model
Not conducted (advanced cancer patient population)
“The Applicant did not conduct carcinogenicity studies based on the proposed patient population.”
Carcinogenicity timing
Not conducted given the advanced-cancer patient population
“The Applicant did not conduct carcinogenicity studies based on the proposed patient population.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: highest doses in rat and monkey 8-cycle studies gave exposures ~8 times lower than human exposure at 3.2 mg/m2
“The highest doses used in the rat and monkey 8-cycle studies resulted in exposures approximately 8 times lower than the human exposure at the recommended dose of 3.2 mg/m2 once every 3 weeks.”
NOAEL / key findings
Injection-site lesions and bone marrow suppression (transient leukopenia, mild anemia) in all species
“The major toxicological findings in all three tested species were injection site findings including hemorrhage, edema, inflammation, thrombosis, and necrosis and bone marrow effects leading to transient leukopenia and mild anemia with decreased cellularity in the bone marrow.”
Efficacy evidenceopen answer page →
Efficacy evidence
Subcutaneous/orthotopic human CDX and PDX tumour xenografts in mice (lung, breast, prostate, ovary, pancreas, sarcoma and others)
“exhibited antitumor activity (decrease in the tumour volume or an increase in the survival time) against different experimental models of either subcutaneously or orthotopically xenografted human cell-derived (CDX) and patient-derived (PDX) tumours such as lung, breast, prostate, bladder, kidney, ovary, pancreas and sarcoma.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
EMA: tumour-microenvironment (transcriptional) effects shown only in vitro at low concentrations, with no in vivo confirmation
“The contribution of sub-lethal transcriptional mechanisms at antitumour doses in vivo remains unclear, as these effects have been demonstrated only in vitro at low concentrations (i.e. there is no in vivo confirmation of these effects).”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
Margins based on MTDs rather than NOAELs; exposure margins well below one in all studies and species
“Regarding the interspecies comparison of exposures and safety margins, these are determined based on Maximal Tolerated Doses (MTDs) for general toxicity studies instead of the NOAELs since the NOAELs were determined only in some toxicology studies (and companion toxicokinetics). Exposure margins at MTDs are well below 1 in all of the performed studies and all of the species.”
GenotoxicityAccepted
No in vivo genotoxicity testing after positive mouse lymphoma assay
Why: ICH S2 provision for strongly cytotoxic compounds targeting rapidly dividing cells · Within the guideline
“In vivo testing was not conducted, but this is acceptable under ICH S2 for strongly cytotoxic compounds targeting rapidly dividing cells.”
DARTAccepted
No definitive embryo-fetal study; only a preliminary single-dose, single-dose-level rat study
Why: Genotoxic mechanism targeting rapidly dividing cells · Within the guideline · Pharmacology or kinetics
“Given its mechanism of action as a genotoxic agent targeting rapidly dividing cells, FDA would not generally request an embryofetal development study, however, the Applicant did conduct a preliminary single dose, single-dose level embryo-fetal development study in rats.”
Impurity or metaboliteAccepted
Human major metabolites not fully covered toxicologically; disproportionate metabolite not studied further
Why: ICH S9 Q&A states no additional studies are required for disproportionate metabolites · Within the guideline
“However, no further non-clinical concern is raised due to: (i) absence of a full toxicological coverage of both human major metabolites (see discussion above), and (ii) ICH S9 Q&A, stating that no additional studies are required with disproportional metabolites.”
Similar precedents
AugtyroSmall molecules · repotrectinib · ROS1/TRKMonkey + rodent · 13 wkAvmapki Fakzynja Co-packSmall molecules · avutometinib and defactinib · RAF/MEK clamp; FAKMonkey + rodent · 13 wkFotivdaSmall molecules · tivozanib · VEGFR1-3Monkey + rodent · 39 wkGavretoSmall molecules · pralsetinib · RETMonkey + rodent · 13 wkHyrnuoSmall molecules · sevabertinib · HER2 (mutant)Monkey + rodent · 13 wkIbtroziSmall molecules · taletrectinib · ROS1Monkey + rodent · 12 wk